Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination

Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination

Impaired contractility after myocardial infarction (MI) causes cardiogenic shock. MARK4 activity impairs contractility post-MI by increasing α-tubulin detyrosination. We assessed the impact of naringenin, a small-molecule MARK4 inhibitor, on contractility post-MI. Naringenin (Nar) was encapsulated i...

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Main Authors: Noah Weingarten, Amit Iyengar, Jessica Dominic, Danika Meldrum, Andrew Belec, Sara Guevara-Plunkett, Rachel Wilson, Joyce Ho, Mrinal Patel, Chaitanya Karimanasseri, Ahmad Amirshaghaghi, Daphne Nie, Benjamin W. Lee, Deborah M. Eaton, Kenneth B. Margulies, Zhiliang Cheng, Andrew Tsourkas, Pavan Atluri
Format: Article
Language:English
Published: MDPI AG 2024-12-01
Series:Applied Sciences
Subjects:
naringenin
MARK4
microtubule
inotrope
myocardial infarction
Online Access:https://www.mdpi.com/2076-3417/14/24/11936
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Summary:Impaired contractility after myocardial infarction (MI) causes cardiogenic shock. MARK4 activity impairs contractility post-MI by increasing α-tubulin detyrosination. We assessed the impact of naringenin, a small-molecule MARK4 inhibitor, on contractility post-MI. Naringenin (Nar) was encapsulated in PEG-PCL to augment bioavailability. Wistar rats were randomized to receive either MI + micellized naringenin (0.3 mg/kg) [MI-NarMic], MI + naringenin (0.3 mg/kg) in 1% DMSO [MI-NarDMSO], MI + empty micelle [MI-Mic], MI alone [MI-Untreated], or no MI [Sham]. MI was induced via left anterior descending artery ligation. Invasive hemodynamics with pressure–volume catheterization, cardiomyocyte contractility, and ventricular protein abundance were assessed one day post-MI. A total of 45 rats underwent hemodynamic assessment. MI-NarMic rats demonstrated decreased α-tubulin detyrosination relative to MI-Untreated rats (<i>p</i> < 0.05). Myocytes isolated from peri-infarct tissue had increased contraction and relaxation velocities in MI-NarMic versus MI-Untreated rats (both <i>p</i> < 0.0001). MI-NarMic rats had higher ejection fractions than MI-Mic and MI-Untreated rats (63 ± 3% v. 48 ± 5% vs. 39 ± 4%, <i>p</i> < 0.05) and similar levels to Sham (61 ± 1%, <i>p</i> = 0.97) and MI-NarDMSO (54 ± 5%) rats (<i>p</i> > 0.05). MI-Nar rats had greater stroke work and lower end-diastolic pressure and tau than MI-Untreated rats (all <i>p</i> < 0.05). Micellized naringenin is a translatable agent with the potential to rescue hemodynamics post-MI by inhibiting MARK4 and mitigating myocardial α-tubulin detyrosination.
ISSN:2076-3417

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